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Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling

Georgia Gunner1, Lucas Cheadle2, Kasey M Johnson1

  • 1Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA, USA.

Nature Neuroscience
|June 19, 2019
PubMed

Insights

Neuron-derived fractalkine (CX3CL1) signals through CX3CR1 on microglia to eliminate synapses after cortical injury. This pathway is crucial for brain synaptic remodeling and immune responses.

Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • Microglia, the brain's immune cells, dynamically regulate synaptic connectivity in response to neural activity and inflammation.
  • The specific extracellular signals, especially those from neurons, that guide microglial synapse regulation are not fully understood.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying microglia-mediated synapse elimination in the cortex.
  • To identify neuron-derived signals and their receptors involved in cortical synaptic remodeling.

Main Methods:

  • Whisker lesioning in mice to induce changes in cortical activity.
  • Analysis of synapse elimination in wild-type and genetically modified mice (Cx3cr1-/-, Cx3cl1-/-).
  • Single-cell RNA sequencing to identify gene expression changes in neurons and microglia.
  • Inhibition of ADAM10 metalloprotease activity.

Main Results:

  • Whisker lesioning triggers microglia-dependent synapse elimination, dependent on CX3CR1 signaling.
  • Mice lacking CX3CL1 exhibit significant defects in synapse elimination.
  • Single-cell RNA sequencing identified cortical neurons as the source of Cx3cl1.
  • ADAM10, an enzyme that processes CX3CL1, is upregulated in specific cortical neurons and microglia post-lesioning.
  • Inhibiting ADAM10 mimicked the synapse elimination deficits observed in Cx3cr1-/- and Cx3cl1-/- mice.

Conclusions:

  • Neuron-derived fractalkine (CX3CL1) is a key signal mediating activity-dependent synapse elimination by microglia in the cortex.
  • The CX3CL1-CX3CR1 axis plays a critical role in cortical synaptic remodeling.
  • This study reveals context-dependent immune mechanisms involved in regulating synaptic plasticity in the mammalian brain.

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